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CLINICAL EXPERTISE:
Dr. Chu is director of the ophthalmic pathology service. For information on submitting specimens, see http://neuro.pathology.pitt.edu/webstuff/Eye Consults.html. For information on training in academic neuropathology or ophthalmic pathology, see the Neuropathology website. http://neuro.pathology.pitt.edu/
RESEARCH EXPERTISE:
Audio - 2010 Carnegie Science Awards Profile of Dr. Chu's Research
Cell Biology of Parkinson's Disease: Mitochondrial Quality Control, Kinase Signaling & Autophagy
Dr. Chu's research focuses on mechanisms of neurodegeneration and neuroprotection in Parkinson's and related neurodegenerative diseases. A major focus is delineating why adaptive cellular mechanisms fail to protect neurons. Molecular and biochemical studies in cell culture and mouse models are integrated with studies of diseased human brain tissues. Recent focus has shifted from cell death to mechanisms of mitochondrial quality control and neuritic/synaptic dysfunction at potentially reversible stages.
Work in the Chu laboratory indicates that pathogenic mechanisms related to five models of PD converge on dysregulation of mitochondrial kinase signaling and turnover by autophagy, the process by which cells sequester, degrade and recycle organelles. These include 6-OHDA and MPP+, two parkinsonian neurotoxins, and genetic models based on mutations in PTEN-induced kinase 1 (PINK1), a mitochondrial kinase, the leucine-rich repeat kinase 2 (LRRK 2), a membrane associated multidomain kinase, and ATP13A2, a lysosomal transporter by homology. Analysis of Parkinson disease and Lewy body dementia brain tissues reveal similar alterations in the localization and trafficking of phosphorylated kinases and transcription factors, associated with mitochondrial autophagy, in susceptible populations of neurons early in the disease process.
While there has been growing interest in therapeutic manipulation of autophagy, the potential beneficial or detrimental roles of autophagy in neuronal responses to parkinsonian injury remain undefined. Our work has led to the concept of "autophagic stress," in which imbalanced or excessive induction of autophagy contributes to neuronal dysfunction. We found that PINK1 is essential for maintaining well-functioning mitochondrial networks, and its loss of function results in mitochondrial ROS that triggers compensatory fission and mitophagy responses. Using phosphoproteomic mass spectrometry, we recently identified a novel phosphorylation site on the autophagy protein LC3, with important suppressive effects on neurite degeneration caused by either MPP+ or mutant LRRK2. We have further discovered that mutant LRRK2 causes early dysregulation of post-synaptic mitochondrial homeostasis and function that precede autophagic neurite degeneration. Current efforts include defining novel phosphorylation sites and signals that regulate selective mitophagy and mitochondrial biogenesis.
Techniques: Protein biochemistry, molecular cell biology, mass spectrometry and phospho-proteomics, quantitative RT-PCR, immunochemistry, multi-label confocal microscopy, electron microscopy, stereotactic brain injections, RNA interference.
Educational initiatives:
Dr. Chu is a member of the Graduate Programs of Experimental Pathology
and Neuroscience (CNUP). She is also a member of the Pittsburgh Institute for Neurodegenerative Diseases (PIND), the McGowan Institute for Regenerative Medicine and the Mitochondria, Metabolism and Disease Working Group.
Dr. Chu is committed to career development of pre-doctoral, post-doctoral and physician-scientist trainees. She organized the 2006 ASIP/FASEB Mentoring Luncheon on "Opening Doors: Networking and Professional Visibility." She developed the Professional Development course designed to introduce MD/PhD students of the University of Pittsburgh and Carnegie-Mellon University to writing and reviewing funding proposals, which is now emulated by other MSTP and graduate programs. She is founding co-director for the Pathologist Investigator Residency/Research Training Program, which is designed to transition physician scientist trainees into academic faculty professorships. This combined Residency-Post-doctoral Research Fellowship is designed to develop Academic Pathologists to become independent Principal Investigators and to play a leading role in combined research and diagnostic careers.
Selected Publications:
(See Dr. Chu's CV for a more complete list and downloads)
View Dr. Chu's recent publications on PubMed
View Dr. Chu's previous publications on PubMed
AM Gusdon, J Zhu, B Van Houten & CT Chu. (2012) ATP13A2 regulates mitochondrial bioenergetics through macroautophagy. Neurobiol Dis 45: 962-972.
RK Dagda, A Gusdon, I Pien, S Strack, S Green, B Van Houten, SJ Cherra III & CT Chu. (2011) Mitochondrially localized PKA reverses mitochondrial pathology and dysfunction in a cellular model of Parkinson's disease. Cell Death Differ 18: 1914-1923.
SJ Cherra III, SM Kulich, G Uechi, M Balasubramani, J Mountzouris, BW Day & CT Chu. (2010) Regulation of the autophagy protein LC3 by phosphorylation. J. Cell. Biol. 190: 533-539. F1000 Recommended: Eui-Ju Choi: Faculty of 1000 Biology, 21 Sep 2010 http://f1000biology.com/article/id/5189958/evaluation
RK Dagda, SJ Cherra III, SM Kulich, A Tandon, D Park & CT Chu. (2009) Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J Biol Chem 284: 13843-13855.F1000 Recommended: Mark A Smith: Faculty of 1000 Medicine, 13 Apr 2010 http://f1000medicine.com/article/n2ld6bdvgcppgvf/id/2890958
EM Chalovich, JH Zhu, J Caltagarone, R Bowser & CT Chu (2006) Functional repression of cAMP response element in 6-hydroxydopamine-treated neuronal cells. J. Biol. Chem, 281: 17870-17881.
JH Zhu, SM Kulich, TD Oury & CT Chu. (2002) Cytoplasmic aggregates of phosphorylated extracellular signal-regulated protein kinases in Lewy body diseases. Am J Pathol 161: 2087-2098.
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